Correspondence

Bosentan in Essential Hypertension

N Engl J Med 1998; 339:346-347July 30, 1998

Article

To the Editor:

Krum and colleagues (March 19 issue)1 make the clinically important observation that the orally active endothelin ET_A- and ET_B-receptor antagonist bosentan causes a sustained reduction of blood pressure in patients with essential hypertension. Although the study was carefully designed and performed, we have some issues of concern related to the interpretation of the results.

First, the authors state that the reduction in blood pressure brought about by bosentan suggests that endothelin-1 contributes to the elevation of blood pressure in patients with essential hypertension, implying causation. However, as the authors note, this study did not test whether patients with hypertension and persons with normal blood pressure differ in their responses to bosentan. This analysis is crucial, because it is already known that endothelin-receptor antagonists produce vasodilatation2-4 and decrease blood pressure3 in persons with normal blood pressure. Indeed, in the only fully reported study in normotensive subjects,3 the placebo corrected reduction in arterial pressure after acute systemic endothelin-receptor antagonism was greater than the response to bosentan in hypertensive subjects.1 Therefore, the hypotensive effects of bosentan may be due to interference with an important physiologic function of endothelin-1 in the maintenance of blood pressure rather than with a specific pathophysiologic mechanism. Nevertheless, endothelin-antagonist drugs may offer important clinical benefits in patients with hypertension, such as reversal of cardiovascular hypertrophy, renal protection, and amelioration of atherosclerosis.5

Second, the authors dismiss endothelial ET_B-receptor blockade as the cause of the rather flat relation between the dose and the blood-pressure–lowering effects of bosentan.1 Nevertheless, it is clear that elevated plasma endothelin-1 concentrations are a marker of ET_B-receptor blockade and that bosentan caused a dose-dependent increase in plasma endothelin-1 in this study. Importantly, recent studies suggest that the principal response of the vascular ET_B receptor to the generation of endogenous endothelin-1 is vasodilatation4 and that the renal tubular ET_B receptor may be important for normal excretion of sodium.5 In this context, the evidence that ET_B-receptor blockade with BQ-788 attenuates vasodilatation to the selective ET_A-receptor antagonist BQ-123 in healthy humans,4 that highly selective ET_B antagonists increase blood pressure in healthy animals,5 and that ET_B knockout mice develop salt-sensitive hypertension5 may be relevant. In the future, it will be important to compare the effects of combined endothelin ET_A- and ET_B-receptor antagonists with those of selective ET_A antagonists.

William G. Haynes, M.R.C.P., M.D.
University of Iowa College of Medicine, Iowa City, IA 52242

Charles J. Ferro, M.B., M.R.C.P.
David J. Webb, M.D., F.R.C.P.
University of Edinburgh, Edinburgh EH4 2XU, United Kingdom

5 References

1. 1

   Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med 1998;338:784-790
   Full Text | Web of Science | Medline

2. 2

   Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344:852-854
   CrossRef | Web of Science | Medline

3. 3

   Haynes WG, Ferro CJ, O'Kane KP, Somerville D, Lomax CC, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 1996;93:1860-1870
   Web of Science | Medline

4. 4

   Verhaar MC, Strachan FE, Newby DE, et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998;97:752-756
   Web of Science | Medline

5. 5

   Webb DJ, Monge JC, Rabelink TJ, Yanagisawa M. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998;19:5-8
   CrossRef | Web of Science | Medline

To the Editor:

In the study by Krum et al., the blood-pressure–lowering effect of bosentan was not associated with activation of the renin–angiotensin system or the sympathetic nervous system. This finding is interesting, because endothelin is known to have inhibitory effects on renin secretion and renal renin gene expression in experimental models.1 The lack of a stimulatory effect on the renal renin system in vivo may be due to a balance between direct inhibition (at the level of the juxtaglomerular cell) and indirect stimulation (e.g., by means of a release of nitric oxide from the endothelium by endogenous endothelins).1,2

Bernhard K. Krämer, M.D.
Frank Schweda, M.D.
Günter A.J. Riegger, M.D.
University of Regensburg, 93042 Regensburg, Germany

2 References

1. 1

   Kramer BK, Schricker K, Scholz H, Clozel M, Riegger GA, Kurtz A. Role of endothelins for renin regulation. Kidney Int Suppl 1996;55:119-121
   

2. 2

   Schricker K, Scholz H, Hamann M, Clozel M, Kramer BK, Kurtz A. Role of endogenous endothelins in the renin system of normal and two-kidney, one clip rats. Hypertension 1995;25:1025-1029
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Haynes and colleagues correctly state, as we implied, that the findings of our study cannot be used to distinguish between a pathologic role for endothelin in hypertension and its role in the regulation of normal blood pressure. The difficulty in addressing this issue is compounded by the fact that endothelin is a paracrine and autocrine peptide released predominantly in an abluminal direction. Therefore, the absence of an elevation in plasma levels (as is the case in many studies of hypertension) does not negate the possibility that endothelin is activated locally and contributes to vasoconstriction in hypertension.

We need comparative studies of endothelin-receptor antagonists in appropriately matched normotensive and hypertensive subjects. The magnitude of short-term lowering of blood pressure with a single dose of an intravenous agent (TAK-044)1 cannot reasonably be compared with that obtained in a four-week study of an orally active agent (bosentan), with measurements of blood pressure taken at trough levels. It is of interest, however, that the same agent (bosentan) produced no sustained lowering of blood pressure in normal subjects when given as a single oral dose.2 This issue does not detract from the potential clinical benefits of endothelin-receptor antagonists in lowering blood pressure and exerting ancillary cardiovascular effects in patients with hypertension.

Haynes and colleagues suggest (as we did) that increasing ET_B-receptor blockade may contribute to the relatively flat blood-pressure dose–response to bosentan. The net effect of ET_B-receptor stimulation on vascular tone remains controversial. Selective ET_B-receptor antagonists have been shown to mediate both vasoconstriction (in a number of studies) and vasodilatation.3 In addition, a selective ET_B-receptor agonist, sarafotoxin S6c, appears to have a vasoconstrictor action in humans.4 In any event, it is unlikely that the full effect of ET_B blockade has been explored with bosentan in our study since the compound has a very high selectivity for ET_A and ET_B receptors. Increasing plasma endothelin levels cannot be used as a surrogate measure of ET_B-receptor blockade, since levels also increase with the administration of ET_A-selective agents.5 The only meaningful way to address this issue is to explore and compare the full dose–response curves of mixed and ET_A-selective endothelin-receptor antagonists in relevant cardiovascular disease states.

With reference to the inhibition of renin secretion by endothelin, this effect has been demonstrated in vitro and in the isolated perfused rat kidney. However, the administration of exogenous endothelin has produced variable effects on plasma renin levels in intact animal models. This latter finding probably reflects the influence of multiple interdependent factors that may affect renin secretion, including afferent renal arteriolar perfusion pressure and filtered sodium load as well as potassium, angiotensin II, aldosterone, and natriuretic peptide status. The sympathetic nervous system is also a key influence, and sympathetic responses to the lowering of blood pressure were attenuated by bosentan in our study. This attenuation may act to dampen any direct effect of endothelin-receptor blockade on renin release.

Henry Krum, M.B., Ph.D.
Monash University, Alfred Hospital, Prahran, Victoria 3181, Australia

Yves Lacourciere, M.D.
Centre Hospitalier Universitaire de Québec, Quebec, QC G1R 2J6, Canada

Vincent Charlon, Ph.D.
F. Hoffmann–LaRoche, Basel CH-4070, Switzerland

5 References

1. 1

   Haynes WG, Ferro CJ, O'Kane KP, Somerville D, Lomax CC, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 1996;93:1860-1870
   Web of Science | Medline

2. 2

   Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996;60:124-137
   CrossRef | Web of Science | Medline

3. 3

   Clozel M, Breu V. The role of ETB receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ETB receptor antagonist Ro 46-8443. FEBS Lett 1996;383:42-45
   CrossRef | Web of Science | Medline

4. 4

   Love MP, Haynes WG, Gray GA, Webb DJ, McMurray JJ. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996;94:2131-2137
   Web of Science | Medline

5. 5

   Spinale FG, Walker JD, Mukherjee R, Iannini JP, Keever AT, Gallagher KP. Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits: beneficial effects on left ventricular and myocyte function. Circulation 1997;95:1918-1929
   Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Ariela Benigni, Norberto Perico, Giuseppe Remuzzi. (2004) The potential of endothelin antagonism as a therapeutic approach. Expert Opinion on Investigational Drugs 13:11, 1419-1435
   CrossRef

2. 2

   Koh Ono, Akira Matsumori. (2002) Endothelin Antagonism with Bosentan: Current Status and Future Perspectives. Cardiovascular Drug Reviews 20:1, 1-18
   CrossRef

3. 3

   Huy Hao Dao, Pierre Moreau. (2001) An update on the status of endothelin receptor antagonists for hypertension. Expert Opinion on Investigational Drugs 10:11, 1937-1946
   CrossRef

4. 4

   Huy Hao Dao, Pierre Moreau. (1999) Endothelin receptor antagonists: novel agents for the treatment of hypertension?. Expert Opinion on Investigational Drugs 8:11, 1807-1821
   CrossRef

5. 5

   Ariela Benigni, Giuseppe Remuzzi. (1999) Endothelin antagonists. The Lancet 353:9147, 133-138
   CrossRef

6. 6

   Pierre Moreau, Ton J. Rabelink. (1999) Endothelin and its antagonists in hypertension: Can we foresee the future?. Current Hypertension Reports 1:1, 69-78
   CrossRef